Experimental

Melting points were determined on a Kofler Block and are uncorrected. Elemental
analyses were carried out in the micro analytical laboratory of the faculty of science,
Cairo University. The IR spectra of compounds were recorded on a Tensor 37 Bruker
infrared spectrophotometer as potassium bromide pellets and frequencies are reported
in cm-1 of the faculty of science, Alexandria University. The 1H NMR spectra were
recorded on a Bruker AC (500 MHz) spectrometer of the faculty of science, Jordan
University. Chemical shifts δ are in ppm and Hz relative to tetramethylsilane as internal
standard. Mass spectra were recorded at 70 ev by 5980 series II GC coupled with 5989
B mass spectrometer of the faculty of science, Cairo University. Reactions were
routinely followed by thin layer chromatography (TLC) using Merck Kiesel gel; 60-
F254 precoated plastic plates. The spots were detected by UV Lamp exposition to light.

Quinazolin-4(3H)-one (1):
A solution of 2-aminobenzoic acid (10 g, 0.0729 mol) and formamide (50 mL) was
heated under reflux for 90 minutes. The reaction mixture was cooled and the solid that
separated out was filtered, washed with methanol, dried and crystallized from methanol
to give the title compound (1)51-53 as colorless needles (10 g, 93% yield); m.p. and
mixed m.p. 186-188°C.

Ethyl 2-(4-oxoquinazolin-3(4H)-yl) acetate (2):

To a solution of quinazolin-4(3H)-one (1, 5g, 0.0344 mol) in dry dimethyl-

formamide (20 mL), anhydrous potassium carbonate (10 g, 0.0723 mol) and ethyl
bromoacetate (5 mL) was stirred at room temperature for 6 hrs. the solid mass poured
onto crushed ice and the product was filtered, washed well with water, dried and
crystallized from ethanol to give the title compound (2) as colorless needles (7.3 g, 92%
yield); m.p. 68-70°C; IR: 1739 (COOEt) and 1676 cm-1 (amide group of quinazolinone
ring); 1H NMR (CDCl3): δ 1.35 (t, 3H, -CH2CH3), 4.31 (q, 2H, CH2CH3), 4.35 (s, 1H,
CH2CO), 7.55 (t, 1H, aromatic-H), 7.82 (t, 1H, aromatic-H), 7.76 (d, 1H, aromatic-H),
8.35 (d, 1H, aromatic-H) and 8.02 (s, 1H, pyrimidine-H); MS: (m/z, %): 232 (M+, 5),
187 (M+ -OEt, 6), 186 (M+ -OC2H6, 7), 160 (M+ -C3H4O2, 3), 159 (M+ -C3H5O2, 32),
103 (M+ -C4H7O3N,2), 102 (M+ -C4H8O3N, 5), 114 (M+-C7H4NO, 30) and 85 (M+ -

—201—
C9H9NO, 15); Anal. Calcd for C12H12N2O3 (232.24): C, 62.06; H, 5.21; N, 12.06 %.
Found: C, 62.30; H, 5.03; N, 12.40%.

N-(2-Hydroxyethyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide (3):

A solution of ethyl 2-(4-oxoquinazolin-3(4H)-yl)acetate (2, 2.32 g, 0.01 mol) and

2-aminoethanol (1.2 g, 0.02 mol) in ethanol (40 mL) was heated under reflux for 3 hrs.
The reaction mixture on cooling gave a solid mass, which was filtered off, washed with
ethanol and crystallized from ethanol to give the title compound (3) as colorless needles
(2.0 g, 81% yield); m.p. 228-230°C; IR: 3582 (OH), 3364 (NH), 1760 (carbonyl group
of quinazolinone ring) and 1670 cm-1 (carbonyl absorption band of amide group); 1H
NMR (DMSO-d6): δ 3.18 (q, 2H, CH2CH2), 3.43 (q, 2H, CH2CH2), 4.74 (t, 1H, OH),
8.38 (t, 1H, NH), 4.68 (s, 2H, CH2CO), 7.55 (t,1H,aromatic-H), 7.84 (t, 1H, aromatic-
H), 7.70 (d, 1H, aromatic-H), 8.17 (d, 1H, aromatic-H) and 8.30 (s, 1H, pyrimidine-H);
MS: (m/z, %): 247 (M+, 49), 202 (M+- C2H4OH, 12), 201 (M+-C2H5OH, 100), 133 (M+-
C4H6N2O2, 15), 132 (M+-C4H7N2O2, 1) and 105 (M+ -C5H6N2O3, 10); Anal. Calcd for
C12H13N3O3 (247.25): C, 58.29; H, 5.30; N, 16.99 %. Found: C, 58.53; H, 5.14; N,
17.23%.

3-(2-Oxopyrrolidin-3-yl)quinazolin-4(3H)-one (4):

A mixture of N-(2-hydroxyethyl)-2-(4-oxoquinazolin-3(4H)-yl)acetamide (3, 0.24

g, 0.001 mol) in conc. Sulfuric acid (10 ml) was stirred at room temperature for 6 hrs.
The reaction mixture was poured onto ice, stirred for 15 min. and neutralized with 30%
aqueous sodium hydroxide. The product was filtered off, washed with water and
crystallized from dioxan to give the title compound (4) as colorless needles (0.1 g, 48%
yield); m.p. 290-292ºC; IR: 3293 (NH) , 1683 (carbonyl group of quinazolinone ring)
and 1658 cm-1 (carbonyl absorption band of pyrrolidine ring); MS: m/z (%): 229 (M+,
4), 228 (M+-H, 48),211 (M+-H2O, 10), 210 (M+-H3O, 100) and 152 (M+-C6H5, 22);
Anal. Calcd for C12H11N3O2 (229.23): C, 62.87; H, 4.84; N, 18.33 %. Found: C, 62.73;
H, 5.00; N, 18.45%.

2-(4-Oxoquinazolin-3(4H)-yl)acetohydrazide (5):

A solution of ethyl 2-(4-oxoquinazolin-3(4H)-yl)acetate (2, 5 g, 0.0215 mol) and

hydrazine hydrate (15 mL) in methanol (50 mL) was stirred at room temperature for

—202—
30 min. The product which separated after cooling, was filtered off, washed with
methanol, dried and crystallized from methanol-benzene to give the title compound (5)
as colorless needles (4 g, 85% yield); m.p. 225-226˚C56; IR: 3463 (NH) , 3291 and 3162
(asymmetric and symmetric NH stretching frequencies of the primary amino group)
1680 (carbonyl group of quinazolinone ring) and 1630 cm-1 (carbonyl absorption band
of pyrrolidine ring); MS: (m/z, %): 218 (M+, 91), 203 (M+-NH, 1), 202 (M+-NH2, 9)
,201 (M+-NH3,64), 126 (M+-C6H6N, 100), 125 (M+-C6H7N, 33) , 160 (M+-CON2H2, 8),
142 (M+-C6H4, 15), 114 (M+-C7H4O, 49), 103 (M+-C3H5N3O2, 2), 102 (M+-C3H6N3O2,
15) and 76 (M+-C4H6N4O2, 21); Anal. Calcd for C10H10N4O2 (218.21): C, 55.04; H,
4.62; N, 25.68 %. Found: C, 55.20; H, 4.37; N, 26.09%.

2-(2-(4-Oxoquinazolin-3(4H)-yl)acetyl)hydrazinecarbothioamide
(6):

A mixture of of 2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide (5, 0.87 g, 0.004

mol.) and potassium thiocyanate (1 g, 0.010 mol) was added to 5 mL of water
containing 1 mL of conc. hydrochloric acid. The reaction mixture was warmed on a
water bath for 2 hrs. Then cooled, poured onto crushed ice and the product was filtered
off, washed with water, dried and crystallized from ethanol to give the title compound
(6) as yellow needles (1 g, 90% yield); m.p. 240-242°C; IR: 3411 (NH), 3387 and 3190
(asymmetric and symmetric NH stretching frequencies of the primary amino group),
1689 (carbonyl group of quinazolinone ring), 1662 (carbonyl absorption band of amide
group) and 1301 cm-1 (thiocarbonyl); 1H NMR (DMSO-d6): δ 7.41, 8.06 (s, 2H, 2NH)
9.49,10.49 (s, 2H, NH2), 4.86 (s, 2H, CH2CO), 7.78 (t, 1H, aromatic-H), 7.87 (t, 1H,
aromatic-H), 7.73 (d, 1H, aromatic-H), 8.15 (d, 1H, aromatic-H) and 8.29 (s, 1H,
pyrimidine-H); MS: (m/z, %): 277 (M+, 100), 260 (M+-NH3, 35), 249 (M+-CO, 72) ,
248 (M+-CHO, 17), 230 (M+-SNH, 21) and 159 (M+-C2H4N3OS, 3); Anal. Calcd for
C11H11N5O2S (277.30): C, 47.64; H, 4.00; N, 25.26; S, 11.56 %. Found: C, 47.36; H,
4.20; N, 25.18; S, 11.95%.

—203—
3-[(5-Thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (7):

Method A:

To a solution of (20 mL) of 5% sodium hydroxide, 2-(2-(4-oxoquinazolin-3(4H)-

yl)acetyl)hydrazinecarbothioamide (6, 2.77 g, 0.01 mol) was added and refluxed for 9
hrs. The reaction mixture was cooled, poured onto crushed ice, neutralized with
concentrated hydrochloric acid. The resulting solid was filtered off, washed with water,
dried and crystallized from ethanol to give the title compound (7) as pale yellow
needles (2 g, 77% yield); m.p. 309-310°C; IR: 3450 (NH) , 2352 (SH) , 1670 (carbonyl
group of quinazolinone ring) and 1606 cm-1 (triazole C=N); 1H NMR (DMSO-d6): δ
13.44 (s, 1H, NH), 13.49 (s, 1H, SH), 5.23 (s, 2H, CH2), 7.58 (t, 1H, aromatic-H), 7.87
(t, 1H, aromatic-H), 7.72 (d, 1H, aromatic-H), 8.15(d, 1H, aromatic-H) and 8.46 (s,
1H, pyrimidine-H); MS: m/z (%): 259 (M+, 84), 119 (M+-C4H4N4S, 100), 118 (M+-
C4H5N4S, 94), 91 (M+-C5H4N4SO, 24) and 90 (M+- C5H5N4SO, 90); Anal. Calcd for
C11H9N5OS (259.29): C, 50.95; H, 3.50; N, 27.01; S, 12.37 %. Found: C, 51.27; H,
3.34; N, 27.16; S, 12.92%.

Method B:

A mixture of ethyl 2-(4-oxoquinazolin-3(4H)-yl)acetate (2, 0.23 g, 0.001 mol) and

thiosemicarbazide(0.35 g, 0.002 mol) in dry pyridine (20 mL) was heated under reflux
for 48 hrs. The reaction mixture was then cooled at room temperature and poured onto
crushed ice and acidified with few drops of acetic acid. The formed product was filtered
off, washed with water and crystallized from ethanol to give the title compound (7) as
pale yellow needles (0.08 g, 32 % yield); m.p. and mixed m.p. 309-310° C.

3-[(1,5,6,7a-Tetrahydrothiazolo[2,3-c][1,2,4]triazol-3-
yl)methyl]quinazolin-4(3H)-one (8):

To a mixture of 3-[(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]quina-
zolin-4(3H)-one (7, 0.65 g, 0.0025 mol) and 1,2-dichloroethane (0.0025 mol.) in
isopropanol (10 mL) was added sodium bicarbonate (6.8 g) and potassium hydroxide
solution (30%, 7.5 mL). The reaction mixture was refluxed for 45 hours. Then the

—204—
solvent was distilled off and the residue was treated with potassium hydrate (20%). The
product obtained was extracted with chloroform and crystallized from chloroform-
methanol to give the title compound (8) as yellow needles (0.5 g, 70% yield); m.p. 256-
258°C; IR:1742 (carbonyl group of quinazolinone ring) and 1620 (triazole C=N) MS:
(m/z, %): 285 (M+, 3), 147 (M+-C7H8NS, 2) and 185 (M+- C3H4N2S, 4) 30 (M+-
C13H9N3SO, 100); Anal. Calcd for C13H11N5OS (287.34): C, 54.34; H, 4.56; N, 24.37;
S, 11.16 %. Found: C, 54.29; H, 3. 82; N, 24.46; S, 11.63%.

3-[(5,6,7,8a-Tetrahydro-1H-[1,2,4]triazolo[3,4-b][1,3]thiazin-3-
yl)methyl]quinazolin-4(3H)-one (9):

To a mixture of 3-[(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]quina-
zolin-4(3H)-one (7, 0.65 g, 0.0025 mol) and 1,3-dibromopropane (0.0025 mol.) in
isopropanol (10 mL) was added sodium bicarbonate (6.8 g) and potassium hydrate
(30%, 7.5 mL). The reaction mixture was refluxed for 45 hrs. Then the solvent was
distilled off and the residue was treated with potassium hydroxide solution (20%). The
product obtained was extracted with chloroform and crystallized from chloroform-
methanol to give the title compound (9) as yellow needles (0.5 g, 67% yield); m.p.
>360°C; IR: 1702 (carbonyl group of quinazolinone ring) and 1590 (triazole C=N);
MS: (m/z, %): 299 (M+, 1), 168 (M+-C8H5NO, 11), 167 (M+-C8H6NO, 100) , 125 (M+-
C11H12NO, 17) and 134 (M+-C9H9OS, 17); Anal. Calcd for C14H13N5OS (301.37): C,
55.80; H, 5.02; N, 23.24; S, 10.64 %. Found: C, 56.40; H, 4.68; N, 23.10; S, 11.29%.

3-[(6-Methyl-5.6,7,8a-tetrahydro-5H-[1,2,4]triazolo[3,4-b]-
[1,3,5]thiadiazin-3-yl)methyl]quinazolin-4(3H)-one (10):

A mixture of 3-[(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (7, 1.55 g, 0.006 mol), formaldehyde (0.014 mol), methylamine (0.006 mol)
was dissolved in ethanol and ethanol-hydrochloric acid (10 mL). The solution was
stirred for 37 hours at 55˚C and laid overnight, then the solvent was removed giving a
solid. The solid was washed with sodium bicarbonate (3%) and crystallized from
methanol to give the title compound (10) as yellow needles (1.4 g, 74% yield); m.p.
330-332°C; IR: 1667 (carbonyl group of quinazolinone ring) and 1605 (triazole C=N);
MS: (m/z, %): 314 (M+, 100), 238 (M+ -C6H4,5), 237 (M+ -C6H5, 34) , 209 (M+ -C7H5O,
20), 159 (M+ -C5H7N4S, 2) and 145 (M+ -C6H9N4S, 3); Anal. Calcd for C14H14N6OS

—205—
(316.38): C, 53.15; H, 5.10; N, 26.56; S, 10.13 %. Found: C, 53.25; H, 4.80; N, 26.83;
S, 10.75%.

3-[(5-Amino-1,3,4-thiadiazol-2-yl)methyl]quinazolin-4(3H)-one
(11):

Method A:

A mixture of 2-(2-(4-oxoquinazolin-3(4H)-yl)acetyl)hydrazinecarbothioamide
(6, 0.36 g, 0.0013 mol) in cold concentrated sulfuric acid (4 mL) was stirred for 10 min.
Then, the reaction mixture was allowed reach to cool at room temperature. After stirring
for an additional 30 min., the resulting solution was poured onto ice-cold water and
made alkaline to pH 8 with ammonia. The precipitated product was filtered off, washed
with water, dried and crystallized from ethanol to give the title compound (11) as
colorless needles (0.25 g, 74% yield); m.p. 260-262°C; IR: 3741 and 3608 (asymmetric
and symmetric NH), 1664 (carbonyl group of quinazolinone ring) and 1616 cm-1
(thiadiazole C=N); 1H NMR (DMSO-d6): δ 7.23 (s, 2H, NH2), 4.45 (s, 2H, CH2CO),
7.59 (t, 1H, aromatic-H), 7.87 (t, 1H, aromatic-H), 7.74 (d, 1H, aromatic-H), 8.19 (d,
1H, aromatic-H) and 8.51 (s, 1H, pyrimidine-H); MS: (m/z, %): 259(M+, 1), 186 (M+-
CHN2S, 100), 185 (M+-CH2N2S, 1) and 122 (M+-C7H7NS, 55); Anal. Calcd for
C11H9N5OS (259.29): C, 50.95; H, 3.50; N, 27.01; S, 12.37 %. Found: C, 51.23; H,
3.65; N, 27.20; S, 12.92%.

Method B:

2-(2-(4-Oxoquinazolin-3(4H)-yl)acetyl)hydrazinecarbothioamide (6, 0.00089

mol) was added gradually to anhydrous orthophosphoric acid (8 mL) in about 5 min.
The reaction mixture was heated in an oil bath at 120˚ for 2 hrs. The slurry thus obtained
was poured onto crushed ice. The solid product was filtered off, washed with cold
distilled water (3x8 mL), dried and crystallized from ethanol to give the title compound
(11) as colorless needles (65% yield); m.p. and mixed m.p. 260-262°C

—206—
1-(5-[(4-Oxoquinazolin-3(4H)-yl)methyl]-1,3,4-thiadiazol-2-yl)-3-
phenylthiourea (12):

To a suspension of 3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]quinazolin-4(3H)-
one (11, 0.26 g, 0.001 mol) in dry dioxan (5 mL) containing anhydrous potassium
carbonate (0.14 g, 0.001 mol) and phenylisothiocyanate (0.001 mol) was added. The
reaction mixture was refluxed for 48 hours, cooled then poured into ice-cold water. The
precipitate obtained was filtered off, washed with water, dried and crystallized from
dimethylformamide-ethanol to give the title compound (12) as brown needles (0.28 g,
72% yield); m.p. 160-162°C; IR: 3865, 3580 (NH), 1673 (carbonyl group of quina-
zolinone ring) and 1611 (thiadiazole C=N); MS: (m/z, %): 394 (M+, 40), 361 (M+-SH,
54), 156(M+-C13H10CNNS, 24), 155(M+-C13H11CNNS, 12), 141 (M+-C14H11N3S, 49),
199 (M+-C8H7N2S2, 13), 198 (M+-C8H8N2S2, 69) and 197 (M+-C8H9N2S2, 100); Anal.
Calcd for C18H14N6OS2 (394.47): C, 54.81; H, 3.58; N, 21.30; S, 16.26 %. Found: C,
54.58; H, 3.40; N, 21.19; S, 16.64%.

1-(5-[(4-Oxoquinazolin-3(4H)-yl)methyl]-1,3,4-thiadiazol-2-
yl)thiourea (13):

A solution of 3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]quinazolin-4(3H)-one
(11, 0.26 g, 0.001 mol) in water and warmed with dilute hydrochloric acid (0.05 mL)
until a clear solution was obtained. Then added ammonium thiocyanate (0.1 g) into
obtained solution dissolved in water (10 mL) gradually. The reaction mixture was
boiled and evaporated to less than half of its volume. It was then cooled to get the
precipitate which were filtered off, washed with water, dried and crystallized from
methanol to give the title compound (13) as pale yellow needles (0.2 g, 63 % yield);
m.p. 112-114°C; IR: 3859 (-NH), 2923 and 2780 (asymmetric and symmetric NH),
1690 (carbonyl group of quinazolinone ring), 1618 (thiadiazole C=N) and 1312 cm-1
(thiocrbonyl); MS: (m/z, %): 318 (M+, 8), 271 (M+-NSH, 13), 134 (M+-C7H8N2S2, 43),
199 (M+-C2H3N2S2, 10) and 198 (M+-C2H4N2S2, 100); Anal. Calcd for C12H10N6OS2
(318.38): C, 45.27; H, 3.17; N, 26.40; O, 5.03; S, 20.14 %. Found: C, 45.50; H, 3.34;
N, 26.31; S, 20.58%.

—207—
3-[(5-{(Hydroxyethynyl)amino}-1,3,4-thiadiazol-2-yl)methyl]
quinazolin-4(3H)-one (14):

To a stirred ice cold suspension of 3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]-

quinazolin-4(3H)-one (11, 0.26 g, 0.001mol) in dry pyridine (5 mL), chloro acetic acid
(0.14 g, 0.0015 mol) was added drop wise. Stirring was maintained at room temperature
for an overnight, then poured into ice-cold water. The obtained precipitate was filtered,
washed with water and crystallized from dimethyl formamide to give the title
compound (14) as brown needles (0.22 g, 73% yield); m.p. 302-304°C; IR: 3650 (OH),
3075 (NH) and 1663 cm-1 (carbonyl group of quinazolinone ring); 1H NMR (DMSO-
d6): δ 7.25 (s, 2H, NH, OH), 5.45 (s, 2H, CH2), 7.59 (t, 1H, aromatic-H), 7.87 (t, 1H,
aromatic-H), 7.73(d, 1H, aromatic-H), 8.19 (d, 1H, aromatic-H) and 8.51 (s, 1H,
pyrimidine-H); MS: (m/z, %): 299 (M+, 1), 204 (M+-C3HN3O, 54), 203 (M+-C3H2N3O,
100), 185 (M+-C3H2N2SO, 21), 159 (M+-C4H2N3SO, 2), 130 (M+-C5H5N4SO, 38) and
144 (M+-C4HN3O2S, 75); Anal. Calcd for C13H9N5O2S (299.31): C, 52.17; H, 3.03; N,
23.40; S, 10.71 %. Found: C, 52.37; H, 3.34; N, 23.29; S, 10.35%.

3-[(6-(Aryl)-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
methyl]quinazolin-4(3H)-one (15a,b):

General procedure

A mixture of 3-[(5-amino-1,3,4-thiadiazol-2-yl)methyl]quinazolin-4(3H)-one (11,

0.078 g, 0.0003 mol) and phenacyl bromide or 4-bromophenacyl bromide (0.15 g,
0.0007 mol.) in absolute ethanol (10 mL) was heated under reflux for 84 hrs. The
reaction mixture was slowly quenched onto crushed ice with stirring and it was
neutralized with sodium bicarbonate solution. The precipitate which separated after
standing overnight was filtered off, washed with cold water, dried and crystallized from
methanol to give the title compound (15a,b) as brown needles.

—208—
3-[(6-Phenyl-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-
methyl]quinazolin-4(3H)-one (15a):

Yield (0.08 g, 74 %), m.p.129-130°C; IR: 1665 (carbonyl group of quinazolinone

ring) and 1604 cm-1 (thiadiazole C=N); MS: (m/z, %): 359 (M+, 1), 302 (M+-CHON2,
9), 140 (M+-C9H7N4OS, 47) and 200 (M+-C9H7N2O, 4); Anal. Calcd for C19H13N5OS
(361.42): C, 63.14; H, 4.18; N, 19.38; S, 8.87 %. Found: C, 63.81; H, 3.58; N, 19.83;
S, 8.66%.

3-[(6-(4-Bromophenyl)-5,6-dihydroimidazo[2,1-b][1,3,4]thiadiazol-2-
yl)methyl]quinazolin-4(3H)-one (15b):

Yield (0.08 g, 62 %); m.p. 221-222°C; IR: 1665 (carbonyl group of quinazolinone
ring) and 1604 cm-1 (thiadiazole C=N); 1H NMR (DMSO-d6): δ 5.65 (s, 2H, CH2), 7.59
-8.21 (multiple, 8H, aromatic-H), 8.62 (s, 1H, imidazole -H) and 8.73 (s, 1H,
pyrimidine-H); Anal. Calcd for C19H12BrN5OS (440.32): C, 51.83; H, 3.20; Br, 18.15;
N, 15.91; S, 7.28 %. Found: C, 52.34; H, 2.57; Br, 18.71; N, 16.16; S, 7.93%.

2-(4-Oxoquinazolin-3(4H)-yl)-N'-(4-oxothiazolidin-2-ylidene)aceto-
hydrazide (16):

To a suspension of 2-(2-(4-oxoquinazolin-3(4H)-yl)acetyl)hydrazinecarbothio-
amide (6, 1.39 g, 0.005 mol.) in absolute ethanol (20 mL), ethyl bromoacetate (0.84 g,
0.005 mol) and (1.64 g, 0.02 mol) anhydrous sodium acetate were added. The reaction
mixture was refluxed in water bath for 20 hrs, cooled, diluted with water and allowed
to stand overnight. The precipitate obtained was filtered off, washed with ethanol, dried
and crystallized from ethanol to give the title compound (16) as yellow needles (1 g,
66% yield); m.p. 260-262°C; IR: 3458, 3256 (2NH), 1760 (carbonyl group of
quinazolinone ring), 1691 (carbonyl group of thiazolidinone) and 1675 cm-1 (carbonyl
group of amide absorption); 1H NMR (DMSO-d6): δ 10.57, 10.65 and 11.87 (s, 2H, -
2NH), 4.83, 4.90 (s, 2H, CH2), 4.01, 4.05 (s, 2H, S-CH2) ,7.57 (t, 1H, aromatic-H), 7.86
(t, 1H, aromatic-H), 7.72 (d, 1H, aromatic-H), 8.15 (d, 1H, aromatic-H) and 8.33 (s,
1H, pyrimidine-H); MS: (m/z, %): 317(M+, 1), 179 (M+-C7H6OS,61), 124 (M+-
C9H7NO2S, 8), 123 (M+-C9H8NO2S, 92), 138 (M+-C9H9NSO, 72), 111 (M+-C9H8N3SO,

—209—
7) and 110 (M+-C9H9N3SO, 100); Anal. Calcd for C13H11N5O3S (317.32): C, 49.21; H,
3.49; N, 22.07; S, 10.10 %. Found: C, 49.43; H, 3.66; N, 22.30; S, 10.48%.

Potassium 2-(2-(4-oxoquinazolin-3(4H)-yl)acetyl)hydrazinecarbodi-
thioate (17):

To a solution of potassium hydroxide (0.84 g, 0.015 mol) in absolute ethanol (250

mL), 2-(4-oxoquinazolin-3(4H)-yl)acetohydrazide (5, 2.18 g, 0.010 mol) and carbon
disulfide (1.14 g, 0.015 mol) in absolute ethanol (250 mL) was added. The reaction
mixture was agitated for 16 hrs, where upon a yellow precipitate was separated. Dry
ether (200 mL) was then added to complete the precipitation of the formed salt. The
obtained product was collected by filtration, washed with dry ether and dried in a
desiccator.

3-[(4-Amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (18):

A suspension of potassium hydrazinecarbodithioate (17, 3.32 g, 0.01 mol) and

hydrazine hydrate (95%, 1 ml, 0.02 mol) in water (5 mL) was heated and stirred under
reflux for 48 hrs. The color of the reaction mixture changed to green, hydrogen sulfide
evolved and homogenous solution resulted. The reaction mixture was cooled, diluted
with ice-cold water (100 mL) and subsequent acidification with conc. hydrochloric acid
gave a white precipitate. It was collected by filtration, washed with ice-cold water (100
mL), dried and crystallized from ethanol to give the title compound (18) as colorless
needles (2.3 g, 84% yield); m.p. 229-230°C; IR: 3443 and 3400 (2NH2), 2658 (SH),
1678 (carbonyl group of quinazolinone ring) and 1602 cm-1 (triazole C=N); 1H NMR
(DMSO-d6): δ 5.78 (s, 2H , NH2), 13.78 (s, 1H, SH), 5.38 (s, 2H, CH2) , 7.58 (t, 1H,
aromatic-H), 7.87 (t, 1H, aromatic-H), 7.73 (d, 1H, aromatic-H), 8.15 (d, 1H, aromatic-
H) and 8.47 (s, 1H, pyrimidine-H); MS: (m/z, %): 274 (M+, 20), 156 (M+-C2H4N3OS,
21), 119 (M+-C4H5N5S, 38), 118 (M+-C4H6N5S, 65) and 90 (M+-C5H6N5SO, 100); Anal.
Calcd for C11H10N6OS (274.30): C, 48.17; H, 3.67; N, 30.64; S, 11.69 %. Found: C,
48.34; H, 3.55; N, 30.50; S, 12.18%.

—210—
3-[(6-Thioxo-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-
yl)methyl]quinazolin-4(3H)-one (19):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (18, 0.27 g, 0.001 mol), potassium hydroxide (0.6 g, 0.01 mol) and carbon
disulfide (4 mL) in methanol (100 mL), was refluxed for 24 hrs and then evaporated
to dryness and aqueous hydrochloric acid (50% , 50 mL) was added, the product was
filtered off, washed with water, dried and crystallized from ethanol to give the title
compound (19) as yellow needles (0.21 g, 68% yield); m.p. 270-272°C; IR: 3418
(NH), 1680 (carbonyl group of quinazolinone ring), 1618 (triazole C=N) and 1304 cm-
1
(thiocarbonyl); MS: (m/z, %): 316 (M+), 315 (M+-H, 1), 255 (M+-SN2H, 24), 159 (M+-
C3H2N4S2, 1), 91 (M+-C6H4N5S2O, 100), 157 (M+-C9H7N2O, 3), 156 (M+-C9H8N2O,
19) and 124 (M+-C9H8N2OS, 33); Anal. Calcd for C12H8N6OS2 (316.36): C, 45.56; H,
2.55; N, 26.56; S, 20.27 %. Found: C, 45. 75; H, 2.40; N, 26.77; S, 20.73%.

3-[(6-(4-Bromophenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-
yl)methyl]quinazolin-4(3H)-one (20):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (18, 0.27 g, 0.001 mol) and p-bromophenacyl bromide (0.0012 mol) in
absolute ethanol (20 mL) was refluxed for 24 hours. The reaction mixture was slowly
quenched onto crushed ice with stirring and was neutralized with aqueous sodium
bicarbonate. The product which separated after standing overnight was filtered off,
washed with cold water, dried and crystallized from ethanol to give the title compound
(20) as yellow needles (0.35 g, 80% yield); m.p. 232-234°C; IR: 1687 (carbonyl group
of quinazolinone ring) and 1608 (triazole C=N); 1H NMR (DMSO-d6): δ 4.49 (s, 2H,
S-CH2), 5.58 (s, 2H, CH2), 7.54 – 8.18 (multiplet, 8H, C6H5) and 8.45 (s, 1H,
pyrimidine-H); MS: (m/z, %):454 (M+ +2, 9), 452 (M+, 5), 185 (M+ -C9H6N3SBr, 85),
157 (M+-C10H6N3SOBr, 98), 155 (M+-C10H8N3SOBr, 100), 171 (M+-C9H6N4SBr, 50)
and 145 (M+-C11H8N4SBr, 4); Anal. Calcd for C19H13BrN6OS (453.32): C, 50.34; H,
2.89; Br, 17.63; N, 18.54; S, 7.07 %. Found: C, 50.20; H, 3.14; Br, 18.08; N, 18.34; S,
7.50%.

—211—
3-[(6-Phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl]quin-
azolin-4(3H)-one (21a):

To a solution of triazole (18, 2.74 g, 0.01 mol) in dry pyridine (25 mL), benzoyl
chloride (1.4 g, 0.01 mol) were added gradually. The reaction mixture was stirred at
room temperature for 2 hrs and then heated for 24 hrs on water bath. It was then poured
onto crushed ice. The solid product was filtered off, washed with water, dried and
crystallized from dimethyl formamide to give the title compound (21a) as colorless
needles (2.8 g, 78% yield); m.p. 240-242°C; IR: 1685 (carbonyl group of quinazolinone
ring) and 1624 (triazole C=N); MS: (m/z, %): 360 (M+, 1), 159 (M+-C9H6N4S, 2), 158
(M+-C9H7N4S, 12), 215 (M+-C8H5N2O, 3), 140 (M+-C14H8N2O, 47), 139 (M+-
C14H9N2O, 4), 138 (M+-C14H10N2O, 2), 112 (M+-C15H10N3O, 15) and 145(M+-
C11H8N4SBr, 4); Anal. Calcd for C18H12N6OS (360.39): C, 59.99; H, 3.36; N, 23.32; S,
8.90 %. Found: C, 60.23; H, 3.55; N, 23.19; S, 8.40%.

3-[(6-(3-Bromophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-
yl)methyl]quinazolin-4(3H)-one (21b):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (18, 0.27 g, 0.001 mol), m-bromobenzoic acid (0.22 g, 0.0011 mol) and
phosphours oxychloride (5 mL) was refluxed for 7 hrs. The reaction mixture was slowly
quenched onto crushed ice with stirring and neutralized with sodium bicarbonate
solution. The product which separated after standing overnight was filtered off, washed
with cold water, dried and crystallized from methanol to give the title compound (21b)
as yellow needles (0.3 g, 70% yield); m.p. 246-248°C; IR: 3483 (NH), 1673 (carbonyl
group of quinazolinone ring) and 1616 (triazole C=N); 1H NMR (DMSO-d6): δ 5.78 (s,
2H, CH2), 7.54 - 8.74 (multiplet, 8H, aromatic-H) and 8.74 (s, 1H, pyrimidine-H);
Anal.Calcd for C18H11BrN6OS (439.29): C, 49.21; H, 2.52; Br, 18.19; N, 19.13; S, 7.30
%. Found: C, 49.54; H, 2.49; Br, 18.00; N, 19.23; S, 7.68%.

3-[(6-(Phenylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)-
methyl]quinazolin-4(3H)-one (22):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-4-
(3H)-one (18, 0.27 g, 0.001 mol), phenylisothiocyanate (0.001 mol), powdered sodium

—212—
hydroxide (0.05 g) was added in dimethyl formamide (25 mL) was refluxed for 48 hrs.
The reaction mixture was poured onto dilute acetic acid (5%, 15 mL). The obtained
precipitate was filtered off, washed with ethanol, dried and crystallized from dimethyl
lformamide-ethanol to give the title compound (22) as colorless needles (0.25 g, 68%
yield); m.p. 240-242°C; IR: 3483 (NH), 1673 (carbonyl group of quinazolinone ring)
and 1616 (triazole C=N); 1H NMR (DMSO-d6): δ 14.75 (s, 1H, NH), 5.51 (s, 2H, CH2)
, 8.12 and 8.58 (multiplet, 9H, aromatic-H) and 8.62 (s, 1H, pyrimidine-H); MS: (m/z,
%): 375 (M+, 5), 252 (M+-C6H5NS, 27), 195 (M+ -C7H6N3SO, 15), 180 (M+-C13H11N2,
28), 132 (M+-C10H7N6S, 1), 90 (M+-C11H7N7SO, 12), 89 (M+-C11H8N7SO, 6) and 88
(M+-C11H9N7SO, 100); Anal .Calcd for C18H13N7OS (375.41): C, 57.59; H, 3.49; N,
26.12; S, 8.54 %. Found: C, 57.49; H, 3.41; N, 26.46; S, 8.22%.

2-(3-Mercapto-5-[(4-oxoquinazolin-3(4H)-yl)methyl]-4H-1,2,4-
triazol-4-yl)isoindoline-1,3-dione (23):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-4-
(3H)-one (18, 2.74 g, 0.01 mol) and phthalic anhydride (0.01 mol) in butanol (20
mL) was heated under reflux for 36 hrs. The solution was concentrated, was filtered
off, washed with ethanol, dried and crystallized from dimethyl formamide to give the
title compound (23) as colorless needles (2.5 g, 62% yield); m.p. 232-234˚C; IR: 2346
(SH), 1790 (carbonyl group of quinazolinone ring) , 1696, 1676 (carbonyl band of
isoindoline-1,3-dione) and 1612 cm-1 (triazole C=N); MS: (m/z, %): 404(M+, 1), 278
(M+-C3N3OS, 78), 185 (M+-C9H5N3O2S, 2), 159 (M+-C10H5N4O2S, 11), 131 (M+-
C11H7N5O2S, 16), 130 (M+-C11H8N5O2S, 25), 91(M+-C13H7N5O3S, 18) and 77 (M+-
C13H7N6O3S, 100); Anal. Calcd for C19H12N6O3S (404.40): C, 56.43; H, 2.99; N, 20.78;
O, 11.87; S, 7.93 %. Found: C, C, 56.11; H, 3.17; N, 20.60; S, 7.44%.

3-[(4-Oxoquinazolin-3(4H)-yl)methyl]-5H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-7(6H)-one (24):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-
4(3H)-one (18, 0.27 g, 0.001 mol) and chloroacetyl chloride (0.001 mol) in dry dioxan
(15 mL) was stirred at room temperature for 24 hrs. The precipitate solid was filtered
off, washed with ethanol, dried and crystallized from dimethyl formamide to give the
title compound (24) as yellow needles (0.24 g, 77% yield); m.p. 160-162˚ C; IR: 3321

—213—
(NH), 1732 (carbonyl group of quinazolinone ring) , 1689 (carbonyl band of thiadiazine
ring) and 1620 (triazole C=N); MS: (m/z, %): 314 (M+, 82), 203 (M+-C3H3N4O, 24),
171 (M+-C3H3N4OS, 22), 155 (M+-C9H7N2O, 50), 98 (M+ -C11H10N3O2, 12) and 91
(M+-C7H5N5O2S, 100); Anal. Calcd for C13H10N6O2S (314.32): C, 49.67; H, 3.21; N,
26.74; O, 10.18; S, 10.20 %. Found: C, 49.83; H, 3.06; N, 26.90; S, 10.81%.

3-[(4-Oxoquinazolin-3(4H)-yl)methyl]-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazol-6(5H)-one (25):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-4-
(3H)-one (18, 2.74 g, 0.01 mol) and urea (0.013 mol) was heated at 180-190˚C for
10 hrs. The reaction mixture was cooled and poured into sodium hydroxide solution
(5%, 20 mL), then filtered off, and the filtrate was acidified with dilute hydrochloric
acid. The solid product was crystallized from methanol to give the title compound (25)
as yellow needles (2.4 g, 80% yield); m.p. 250-252˚C; IR: 3483 (NH), 1723 (carbonyl
group of quinazolinone ring), 1667 (carbonyl band of thiadiazole ring) and 1572 cm-1
(triazole C=N); MS: (m/z, %): 300 (M+, 3), 269 (M+-HNO, 100), 186 (M+-C2N3OS, H-
migration, 89) and 158 (M+-C3H2N4OS, 22); Anal. Calcd for C12H8N6O2S (300.30): C,
48.00; H, 2.69; N, 27.99; S, 10.68 %. Found: C, 47.70; H, 2.85; N, 28.19; S, 10.21%

3-[(6,7-Diphenyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-
methyl]quinazolin-4(3H)-one (26):

A mixture of 3-[(4-amino-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]quinazolin-4-
(3H)-one (18, 1.37 g, 0.005 mol) and benzoin (1.06 g, 0.005 mol) in ethanol (30 mL)
was heated to get a clear solution and then 2N potassium hydroxide solution (0.5 mL)
was added to the hot solution. The reaction mixture was refluxed with constant stirring
for 120 hrs, then concentrated and cooled to room temperature. The product was filtered
off , washed with water, dried and crystallized from ethanol to give the title compound
(116) as pale yellow needles (1.2 g, 53% yield); m.p. 240-242°C; IR: 3455 (NH), 1680
(carbonyl group of quinazolinone ring) and 1614 (triazole C=N); Anal. Calcd for
C25H18N6OS (450.52): C, 66.65; H, 4.03; N, 18.65; S, 7.12 %.Found: C, 66.54; H, 3.82;
N, 18.80; S, 7.55%.

—214—
—215—